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Hard metal consists of a powder mixture of tungsten carbide (WC,85%) and metallic cobalt (Co,5-15%). WC-Co was evaluated as a probable carcinogen in humans by IARC in 2003. It is believed that the toxicity and carcinogenesis of WC-Co is associated with particle size. Although nanomaterials are currently being widely used in modern technology, there is a serious lack of information concerning human health effects and environmental implications of manufactured nanomaterials. In this report, we investigated the effects of nano- (40-80 nm) and fine (40 um) 85WC/15Co particles on AP-1-mitogen-activated protein kinase (MAPKs) and NF-kB signaling in mouse epidermal (JB6) cells. The results demonstrated that the induction of AP-1 activity by nano-WC-Co was 4-times higher than that stimulated by fine-WC-Co. Similar results were obtained for NF-kB induction. The induction of AP-1 and NF-kB activity in cultured cells was time and dose-dependent. The signal transduction pathways for AP-1 activation were also investigated and the results demonstrated that both nano- and fine-WC-Co stimulate MAPK family members, including extra-cellular signal-regulated protein kinase (ERKs), p38 kinase, and C-Jun N-terminal kinase (JNKs). The potency of nano-WC-Co on MAPKs stimulation was significantly higher than that for fine WC-Co. Electron spin resonance (ESR) studies indicated that nano-WC-Co generated more reactive oxygen species (ROS) than the fine particles when incubated with the cells. Study using ROS- sensitive dyes support the conclusion that ROS are generated by WC-Co-treated cells. N-Acetylcysteine, an antioxidant agent, decreased AP-1 activation and phosphorylation of ERKs, p38 kinase and JNKs, suggest the involvement of ROS in the mechanisms of WC-Co-induced AP-1 activation. These findings demonstrate that WC-Co induces NF-kB and AP-1-MAPKs activation, which may be mediated through ROS. The size of the particles plays a critical role in toxicity and carcinogenicity of the hard metal.